Treatment for cerebral palsy gait impairment

ABSTRACT

A methylphenidate, particularly including dextro-threo-methylphenidate, is administered to a child to treat a gait impairment and a speech impairment secondary to a non degenerative disease or disorder acquired in utero, at birth or in infancy, but later manifested.

PRIOR RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 14/793,829, filed Jul. 8, 2015, which is a divisional application ofU.S. application Ser. No. 14/453,014, filed Aug. 6, 2014, now U.S. Pat.No. 9,155,502, which is a continuation-in-part application of U.S.application Ser. No. 14/059,541, filed Oct. 22, 2013, now U.S. Pat. No.8,883,815, which is a continuation-in-part application of U.S.application Ser. No. 14/112,065, filed Dec. 24, 2013, now U.S. Pat. No.9,089,563, which is a US 371 National Phase application ofPCT/US2012/038312, filed May 17, 2012, which claims priority to U.S.Provisional Application No. 61/487,847, filed May 19, 2011; and

This application Ser. No. 14/793,829, filed Jul. 8, 2015, is acontinuation-in-part application of U.S. application Ser. No.14/736,406, filed Jun. 11, 2015, now U.S. Pat. No. 9,220,712, which is acontinuation-in-part of U.S. application Ser. No. 14/112,065, filed Dec.24, 2013, now U.S. Pat. No. 9,089,563, which application is a US 371National Phase application of Patent Application No. PCT/US2012/038312,filed May 17, 2012, which claims priority to U.S. Provisional PatentApplication Ser. No. 61/487,847, filed May 19, 2011, which applicationsare incorporated herein in their entireties by reference thereto.

FIELD OF THE INVENTION

This invention relates to a pharmaceutical intervention and method fortreating a gait impairment, particularly including a gait impairmentsecondary to cerebral palsy. Specifically, this invention relates to apharmaceutical intervention for a subject with motor deficits in thelimbs. More specifically, this invention also relates to apharmaceutical intervention for treating gait and speech impairmentssecondary to cerebral palsy. More specifically, this invention alsorelates to a pharmaceutical intervention for treating gait abnormalitiesor impairments resultant side effects of anti-cancer and anti-seizuredrugs.

BACKGROUND AND DISCUSSION OF THE PRIOR ART

Cerebral palsy (CP) is a non-progressive disease or disorder involvingirreparably damaged or injured areas of the brain, including connectionsbetween the cortex and other parts of the brain (the central nervoussystem) and the muscles in the peripheral nervous system. The NationalInstitute of Neurological Disorders and Stroke (NINDS) of the NationalInstitutes of Health (NIH) defines cerebral palsy as any of a number ofneurological disorders that appear in infancy or early childhood andpermanently affect body movements and muscle coordination but do notworsen over time, and the NIH makes clear that cerebral palsy cannot becured.

Infantile cerebral palsy (ICP) refers to a disorder affecting movement.Infantile spastic cerebral palsy refers to ICP with spastic motordefects. Generally, infantile spastic cerebral palsy can be separatedinto two groups: (1) the symmetric palsies, including the diplegias,which exhibit symmetric involvement on both sides of all fourextremities but to a greater degree in the legs, and the paraplegias, inwhich the lower extremities are equally involved, and (2) the asymmetricpalsies which include the hemiplegias, monoplegias, triplegias andquadriplegias. The quadriplegias differ from the diplegias in that allfour extremities are more or less irregularly involved often with equalor greater spasticity in the arms.

A most common type of spastic cerebral palsy is spastic diplegia. Mostindividuals with spastic diplegia exhibit scissors gait. Scissors gaitis characterized by adduction and internal rotation at the hip, rigidityand excessive adduction of the leg in swing, flexion at the knee,planton flexion at the ankle and contractions of the spastic muscles.Other cerebral palsy gait impairments include toe down where the toe ispointing down and inward. Such gait impairments result in thetoe-to-heel step as opposed to the correct heel-to-toe step. Toe-to-heelstep in turn causes considerable pain to the individual. Someindividuals may exhibit combinations of such characteristics.

Attempts to treat gait impairments and spasticity include devices suchas a therapeutic chair as disclosed in U.S. Pat. No. 4,145,083, issuedMar. 20, 1979 to Urban; transcranial electrode stimulation as disclosedin U.S. Pat. No. 4,844,075, issued Jul. 4, 1989 to Liss; transcranialmagnetic stimulation as disclosed in US2011/0270345A1, published Nov. 3,2011 to Johnston et al.; neurosurgery as disclosed in U.S. Pat. No.6,936,049, issued Aug. 30, 2005 to Svadovskiy; botulism toxin asdisclosed in U.S. Pat. No. 7,378,389, issued May 27, 2008 to Graham; andcombinations of botulism toxins with automated movement therapy asdisclosed in US 2008/0279896A1, published Nov. 13, 2008, to Heinen etal. Heinen et al. discloses pharmaceutical muscle stimulation prior toand in combination with botulism toxin and in further combination withautomated movement interventions.

Parkinson's disease is a degenerative disorder of the cerebral nervoussystem effecting specific motor systems that result specifically fromthe dearth of dopamine generating in the basal ganglia. Parkinson'sdisease is an idiopathic degenerate disorder that develops usually inindividuals 60 years of age or older. A brain scan of an individual withParkinson's' disease reveals no brain damage, unlike cerebral palsy.Parkinson's disease is characterized by stiffness or rigidity, slow anddecreased movements resulting in gait instability and the readilyrecognizable Parkinson's shuffle. Parkinson's gait rigidity is markedlydistinguished from cerebral palsy spasticity. Insofar as Parkinson'sdisease results from a loss of dopamine, one treatment is theadministration of dopamine agonists particularly methylphenidate, asdisclosed in Methylphenidate for the Treatment of Gait Impairment inParkinson's Disease; NIH Clinical Trials, pp 1-5; Oct. 27, 2009; anddopamine transporter inhibitors, as disclosed in U.S. Pat. No.8,258,305, issued Sep. 4, 2012 to Hauske.

The art desires a treatment for a cerebral palsy gait impairment in oneor both lower limbs that provides persistent improvement in gait anddoes not require mechanical, electro-mechanical, invasive and toxicinterventions.

The art also desires a treatment as aforesaid including apharmacological intervention and method for treating a gait abnormalityor impairment resultant side effect from the administration of ananti-cancer or anti-seizure drug.

The art desires a treatment as aforesaid wherein the impairment isdiminished, and the diminishment in the impairment persists andcontinues over time, even when the pharmaceutical intervention is nolonger efficaciously present.

The art also desires a pharmacological intervention as aforesaid for thesimultaneous treatment of a gait or limb impairment and a speechimpairment, particularly in children, and more specifically includingRett syndrome limb and speech impairments.

The art also desires a pharmacological intervention for a gaitimpairment as aforesaid that is readily administered, efficacious andsafe, with ready and persistent diminishment of the gait abnormality orimpairment. The present invention provides a solution to the aforesaidneeds.

SUMMARY OF THE INVENTION

The present invention, in one aspect, is a pharmaceutical interventionand method for treating a gait impairment in a subject having cerebralpalsy The method includes administering a therapeutically effective doseof a psychostimulant, particularly a norepinephrine dopamine reuptakeinhibitor (NDRI), to the subject to effect gait impairment diminishment.

The present invention, in another aspect, is a pharmaceuticalintervention and method for treating a child with a gait impairment withmotor deficits in one or both lower limbs. The method includesadministering a therapeutically effective dose of a psychostimulant tothe subject to effect diminishment of the gait impairment and reductionof the pain associated with the gait impairment. The diminishment of thegait impairment and reduction in pain persists over time even when thepsychostimulant is no longer efficaciously present.

The present invention, in one further aspect is the combination of afirst medicament that efficaciously treats a disease or disorder but hasan adverse side effect of a gait abnormality or impairment and/or aspeech impairment, and a second medicament that includes apsychostimulant, wherein the combination of medicaments results inavoided or diminished gait or speech impairments. Gait abnormalities andsensory loss impairments resultant from anti-seizure and anti-cancermedicaments are treated by the present invention.

The invention, in a further specific aspect, is a pharmaceuticalintervention and method for treating speech impairments and limbdisorders secondary to Rett syndrome. Rett characteristics particularlyan apraxia of speech and non specific hand-wringing are diminished withthe present pharmaceutical intervention.

The present invention as aforesaid is wherein the pharmaceuticalintervention is an NDRI that has mood elevating or anti-depressantproperties such as a methylphenidate, particularly includingdextro-threo-methylphenidate.

Without wishing to be bound by any theory or mechanism, it is believedthat the administered NDRI, particularly including a methylphenidate,and more particularly dextro-threo-methylphenidate, provides or restoresneural pathways extending from the prefrontal cortex so as to provideimproved management and control of the limbs, particularly the lowerlimbs in turn resulting in improved or corrected gait.

Without wishing to be bound by any theory or mechanism, it is alsobelieved that the methylphenidates administered pursuant to the presentinvention may affect or restore neural pathways between upper motorneural lesion areas of the brain and the spine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the % heel-toe-toe as compared to % toe-to-heel step gaitat the initial administration of a pharmacological intervention of thepresent invention and at the time of a subsequent administration of apharmacological intervention pursuant to the present invention forParticipants 1-5A.

FIG. 2 shows the GMFCS level at the initial time prior to and after apharmacological regimen of the present invention for Participants 1-7.FIG. 2 demonstrates that the GMFCS level number after a regimen of thepharmacological intervention of the present invention is at least onelevel number less than before the regimen.

FIG. 3 is a graph of the time spent holding stair railings while goingup and down stairs in an initial visit/examination before and afterpharmaceutical intervention, and in subsequent visits/examinations forParticipant 5A. The solid line is the within the hour measurements at aspecific visit/examination, and the broken line is the timeframe betweenvisits/examinations.

FIG. 4 is a graph of the time spent in a 30 second timeframe inheel-to-toe walking while going up and down stairs at an initialvisit/examination before and after the initial pharmaceuticalintervention, and in subsequent visits/examinations for Participant 5A.The solid line is the within the hour measurements at a specificvisit/examination, and the broken line is the timeframe betweenvisits/examinations.

FIG. 5 is a graph of the percentage time in correct heel-to-toe gaitwhen walking up and down stairs in an initial visit/examination beforeand after the initial pharmaceutical intervention and in subsequentvisits/examinations for Participant 5B.

FIG. 6 is a graph of the percentage time spent keeping the foot turnedout when walking up and downstairs in an initial visit/examinationbefore and after the initial pharmaceutical intervention and insubsequent visits/examinations for Participant 5B.

FIG. 7 is a graph of the time spent in seconds over a 60 secondtimeframe with the ankle turned inwards and crossing over the ankle whenwalking in an initial visit/examination and in subsequentvisits/examinations for Participant 6.

FIG. 8 is a graph of the distance covered in steps walking on a flatsurface attempting to traverse a course at an initial visit/examination,and traversing the course in subsequent visits/examinations forParticipant 6.

FIG. 9 is the time spent in nonspecific hand wringing while walkingmeasured at visits/examinations during the pharmacological interventionregimen for Participant 6.

FIG. 10 is a graph of the time to place the feet on the ground and pickthe body up from a seated position to standing with a walker invisits/examinations for Participant 7.

FIG. 11 is a graph of time spent to walk 10 feet during the course ofthe pharmacological interventions for Participant 7.

DESCRIPTION OF THE INVENTION

The term “subject” as used hereinbefore and hereinafter means a human orother mammal, and includes a patient, or a participant in a study orclinical trial.

The term “therapeutically effective dose” or “therapeutically effectivedosage” as used hereinbefore and hereinafter means an amount of theadministered substance that is sufficient to provide a diminishment ofthe impairment.

The term “psychostimulant” as used hereinbefore and hereinafter isbroadly defined to include an NDRI having antidepressant ormood-elevating properties, and as further discussed hereinafter.

The terms “MPH” and “MPD” as used hereinbefore and hereinafter refer toracemic methylphenidate.

The term or acronym “GMFCS” means Gross Motor Function ClassificationSystem. The gross motor skills (e.g. sitting and walking) of childrenand young people with cerebral palsy can be categorized into 5 differentlevels using a tool called the Gross Motor Function ClassificationSystem (GMFCS). The GMFCS levels are: Level 1 walks without limitations;Level II walks with limitations. Limitations include walking longdistances and balancing, but not as able as Level I to run or jump; mayrequire use of mobility devices when first learning to walk, usuallyprior to age 4; and may rely on wheeled mobility equipment when outsideof home for traveling long distances; Level III—walk with adaptiveequipment assistance. Requires hand-held mobility assistance to walkindoors, while utilizing wheeled mobility outdoors in the community andat school; can sit on own or with limited external support; and has someindependence in standing transfers; Level IV—self-mobility with use ofpowered mobility assistance. Usually supported when sitting;self-mobility is limited; and likely to be transported in manualwheelchair or powered mobility; and Level V—severe head and trunkcontrol limitations. Requires extensive use of assisted technology andphysical assistance; and transported in a manual wheelchair, unlessself-mobility can be achieved by learning to operate a poweredwheelchair.

The terms “visit”, “examination” or “visit/examination” refer to anexamination of the Participant by a pediatric neurologist.

The present invention includes the administration of a therapeuticallyeffective dose of one or more of a broad range of NDRIs or dopamineagonists including a methylphenidate, particularly includingdextro-threo-methylphenidate, (Focali®), and the non linear lower alkylphenidates, particularly including isopropylphenidate.

The present invention treats subjects, particularly children, diagnosedwith cerebral palsy having secondary disorders including both a gaitimpairment and a speech impairment. The treatment of speech impairmentsecondary to cerebral palsy is disclosed in co-pending application Ser.No. 14/453,014, filed Aug. 6, 2014, and in parent application Ser. No.14/059,541, filed Oct. 22, 2013, now U.S. Pat. No. 8,883,815, whichreferences are incorporated herein in their entireties by referencethereto.

The present invention contemplates a combination of two medicaments, afirst medicament that efficaciously treats a certain disease or disorderbut has an adverse side effect, namely a gait abnormality or impairmentand/or speech impairment, and a second medicament namely apsychostimulant having mood elevating or anti-depressant properties,particularly including a methylphenidate, that diminishes the gait orspeech impairment. The first medicament is typically an anti-cancer oranti-seizure medicament.

It is widely reported that anti-seizure medicaments includingoxcarbazepine (Trileptal®) and cancer treatment medicaments includingthalidomide, thalidomide analogs and Abraxane® have adverse side effectsleading to a pronounced percentage of gait abnormalities or impairmentsand to a much lesser percentage of speech impairments. Anticancerdrug-induced peripheral neurotoxicities are predominately sensory.Sensory loss in the feet and legs can in turn cause sensory ataxia andgait abnormalities or impairments. It is within the contemplation of thepresent invention to combine or co-administer the pharmaceuticalintervention of the present invention with a anti-seizure or cancermedicament.

The art suggests thalidomide can also be used in the treatment of ALS,as disclosed in US Pub. 2005/0182097, published Aug. 18, 2005 to Zeldiset al. Speech impairments are secondary to ALS. The presentpharmaceutical intervention may likewise be used in the thalidomidetreatment of ALS

It is also within the contemplation of the present invention to combineor co-administer thalidomide, thalidomide analogs or Abraxane® with thepsychostimulant of the present invention, particularly methylphenidate,and more particularly dextro-threo-methylphenidate, to efficaciouslytreat the cancer or ALS while diminishing or precluding the gait andspeech impairments.

It has been surprisingly found that the pharmaceutical intervention andmethod of the present invention diminishes the aforesaid impairments,which diminishment in impairments and pain persists even when thepharmaceutical intervention is no longer efficaciously present.

Examples Participant 1

Participant 1 is a male and was 8 years old at the time of the firstpharmacological intervention pursuant to the present invention.Participant 1 had delayed speech and language. Participant 1 wasdiagnosed as having spastic dipligea, bilateral contractures at thehips. Participant 1 wore leg braces prior to the pharmacologicalintervention, and the braces were removed in the initial visit. Prior tothe pharmacological intervention of the present invention, Participant 1was treated with Botox injections, oral baclofen and orthotics. Theparents of Participant 1 stopped all such treatments because they didnot observe any improvement in gait.

The initial pharmacological intervention was 2 cc (10 mg) of QuillivantXR®, and one month later was replaced with 5 mg of racemicmethylphenidate (MPD)/day. FIGS. 1-2 for Participant 1 shows theimprovement in gait after about 45 minutes at the initial visit, andafter daily treatments of 5 mg methylphenidate/day.

Participant 2

Participant 2 is a female and was 15 years old at the time of theinitial pharmacological intervention pursuant to the present invention.Participant 2 did not start to walk until 18 months of age, and hadsignificantly delayed speech and language development. She was notspeaking in sentences until she was 5 years of age.

Participant 2 was diagnosed with spastic dipligea and painful gait. Herweight increased because of the avoidance of walking to preclude theconcomitant pain.

After about one year of daily methylphenidate administrations, she couldwalk on a flat surface and up and down stairs with flexibility, evenwhen the methylphenidate is no longer efficaciously present in the body.

Participant 2 reports she is pain free, has entered the school talentshow and exhibits a 15 minute dance routine performed at school.

Participant 3

Participant 3 is a female and was about 15 years of age at the firstpharmacological intervention pursuant to the present invention.

Participant 3 had an initial diagnosis of cerebral palsy, epilepticencephalopathy, global development delay, left hemiplegia and spasticdipligea, left greater than right. At the initial visit, Participant 3was physically examined and found to have a limited amount of receptiveand expressive language, with the left side of the body much smallerthan the right side, left hemiplegia, contractions of the left elbow,and unable to open left hand, with the fingers and thumb kept in fistedposition. Participant 3 loses balance and falls if not assisted whenrising from a chair. When walking on a flat surface, she keeps her leftelbow at 90 degrees, left hand remains in a fisted position, toe-to-heelgait, bilateral left greater than right. And to avoid tripping over herleft foot, she keeps her left foot in extension securing her left leg asfar away from her trunk in order for her left foot to have enoughclearance to avoid first hitting the ground with the extremities.

A 400 mg/day Gabapentie regimen was prescribed. After 2 months, therewas a 5 mg MPD initial administration. This was followed by 5 mg MPD/dayfor a period of 11 months. FIGS. 1-2 show Participant 3 gait improvementat the initial intervention, and after the 11 months of the foregoingregimen.

Participant 3 reports playing sports, even when the MPD is no longerefficaciously present.

Participant 4

Participant 4 is a female, and was about 19 years of age at the time offirst pharmacological intervention of the present invention. Participant4 was born prematurely at 24 weeks. Participant 4 had a twin. The twindied on day one. Participant 4 suffered hypoxia at birth. Participant 4first began to walk and talk well over 2 years of age. Participant 4 wasdiagnosed with cerebral palsy and global developmental delay,Hashimoto's thyroiditis, epilepsy, scoliosis and spastic dipligea. AnMRI of the brain revealed periventricular leukomalacia. The initialvisit revealed that Participant 4 walks with a crouched gait, flexed atthe hips and knees, lateral fixed contractions, and obligated toe toheel gait with pain when walking and calf muscular pain when notwalking. Medication administered long prior to and during thepharmacological intervention of the present invention included theanti-seizure medicament oxcarbazepine (Trilepal®). Oxcarbazepine(Trilepal®) is reported to cause gait abnormalities as a side effect.

The improvements in gait and step after the two weeks of daily MPDadministration are shown in Table 1.

TABLE I Heel-to-Toe/ Stairs Holding to Railings Up Stairs HoldingRailings Down Toe-to-Heel (Sec./Sec.) (Sec./Sec.) (Sec./Sec.) Initial9.38/15 Initial 7.4/59 Initial 12.81/59 After 2 Weeks   15/15 After 2Weeks   0/60 After 2 Weeks    0/60

Participant 4 Example demonstrates improvements in gait including stepwith co-administration of an anti-seizure medicament having a gaitimpairment side effect.

It is within the contemplation of the present invention to combine thepresent pharmacological intervention with a medicament for treating adisease or disorder but with gait abnormality or impairment sideeffects, whereby the disease or disorder is treated and the impairmentside effects are precluded or diminished, particularly as demonstratedin the Participant 4 Example.

Participant 5A

Participant 5A is a female 13 years of age at the time of the firstexamination pursuant to the present invention. Participant 5A has anidentical twin; hereinafter referred to as Participant 5B. Participants5A and 5B were born to a drug addicted alcoholic woman and werediagnosed with speech and gait impairments secondary to cerebral palsy.Participant 5A had a speech-language disorder and spastic diplegia.Participant 5A had to direct both legs in extension to avoid trippingover her own feet because she was unable to flex and extend at the anklejoint to move her feet, resulting from the spastic dipligea.

At the first visit/treatment, 5 mg of methylphenidate was administeredto Patent 5A. Prior to the administration, Participant 5A had noheel-to-toe functionality. After administration, Participant 5A hadgenerally 43% heel-to-toe walking time in both feet in walking and upand down stairs. See FIG. 1. Participant 5A reported no pain afterwalking.

Referring specifically to FIGS. 3 and 5, there is shown the dramaticimprovement in heel-to-toe steps in traversing stairs, for Participant5A, particularly with a Focalin® regimen in lieu of a racemicmethylphenidate regimen.

Participant 5B

Participant 5B is the identical twin of Participant 5A. Participant 5Bwas diagnosed with severe speech impairment secondary to cerebral palsy.Participant 5B, unlike her twin sister, Participant 5A, did not havequite as severe gait impairment. Participant 5B, however, could not keepher foot straight and had to hold onto railings ascending or descendingstairs.

In the first examination, because the speech impairment was so severe,Participant 5B was diagnosed as mentally retarded. There was novolitional speech. Participant 5B could not read or comprehend at asecond grade level.

In the second examination, a regimen of 5 mg MPD/day was prescribed, tobe taken before school.

At the beginning of the third examination, about one month after thesecond examination, 5 mg MPD was administered. After 40 minutes,Participant 5B had spontaneous speech of 4-6 words, as opposed to the2-3 word capability in the first examination. Participant 56comprehended at a second grade level. A revised regimen of 10 mg MPD/daybefore school was prescribed.

A fourth examination occurred approximately one month after the thirdexamination. Participant 5B was administered 10 mg Focalin®. After 40minutes, Participant 5B was able to keep her foot straight in walkingand did not feel like she was going to fall.

Participant 56 had a regimen of 10 mg/day Focalin® for the next 14 days.A fifth examination was undertaken after the 14 days of Focalin®. At thebeginning of the fifth examination, a 10 mg dose of Focalin® wasadministered. After 45 minutes, Participant 56 had a completeunderstanding of a book that demonstrated comprehension at a 7^(th)grade level. This level of comprehension persisted even when theFocalin® was no longer efficaciously present.

Referring specifically to FIG. 6, there is shown the improvement in thepercentage time keeping the foot turned outwardly as opposed to inwardlytoe down, in traversing stairs for Participant 5B. The improvement ismost dramatic with a Focalin® regimen in lieu of a racemicmethylphenidate regimen.

The Participants 5A and 5B Examples demonstrate diminishments in bothspeech and gait impairments secondary to cerebral palsy. Theimprovements in gait speech and comprehension were particularlysignificant with a regimen of daily administrations of Focalin®.

Participant 6

Participant 6 is a female. At 2-3 years of age she was diagnosed withcerebral palsy.

Participant 6 had an initial visit or examination when she was 8 yearsold. A gait impairment, constant hand wringing and an apraxia of speechwere observed. The gait impairment was a scissors gait with the ankleturning inwards and crossing over when walking.

A 5 mg MPD dose was administered to Participant 6. After 40 minutes,there was a noticeable improvement in gait. A regimen of 5 mg MPD/daywas prescribed and continued for one year, at which time the dose wasincreased to 5 mg MPD/twice daily; once after breakfast and once afterlunch. Observations for Participant 6 in subsequent visits/examinationsare reported in the FIGS. 6-9, and were taken when Participant 6 was offMPD for 24 hours.

In the course of the afore-described treatment, a genetic work-up wasprescribed. It was determined that Participant 6 had a polymorphismheterozygote genetic defect, namely a mutant MECP2 gene. Consequentiallyshe was diagnosed as having Rett syndrome. Participant 6 was observed ashaving a motor apraxia. She exhibited constant nonspecific hand-wringingconsistent with Rett syndrome.

Rett syndrome is a neurodevelopment disorder that affects girls almostexclusively. In nearly all cases of Rett syndrome, there is a mutationin the methyl CpG binding protein 2, or MECP2 gene. The symptoms aregenerally overlooked in the early stages. As the syndrome progresses,the child has jerkiness in limbs and gait impairments, and the childloses purposeful use their hands, characterized as constant hand washingor hand-wringing. In later stages, apraxia and particularly an apraxiaof speech occur. There is no known cure for Rett syndrome, and the lifeexpectancy at best is about 40 years, as reported in the NIH Nationalinstitute of Neurological Disorders and Stroke (NINDS) “Rett SyndromeFact Sheet,” NINDS Pub. November 2002, updated Feb. 23, 2015.

Referring specifically to FIGS. 7-9, there is shown the improvement ingait for Participant 6 in an MPD regimen over the course of a two yearperiod. Participant 6 showed continued improvement in motor planning andexecution, particularly the elimination of ankle inwards and toe downimpairments. Prior to Oct. 17, 2013, Participant 6 was able to traverseonly 25 feet in 60 seconds, and by May 22, 2015, Participant 6 was ableto traverse 66 feet in 60 seconds. These improvements resulted from thediminishment in motor apraxia and elimination of the nonspecifichand-wringing while walking.

As demonstrated in FIG. 2 and FIGS. 7-9, the MPD course of treatmentresulted in a GMFCS improvement from level number 3 to level number 1,essentially a complete diminishment of scissors gait and an essentiallycomplete diminishment of the hand-wringing. Speech language equivalenceimproved dramatically over the course of treatment evidencing ordiminishment of the apraxia of speech.

The Participant 6 Example demonstrates the pharmaceutical treatment oflimb impairments, particularly including nonspecific hand wringing andan apraxia of speech secondary to Rett syndrome.

Participant 7

Participant 7 is a female born in 2004. The first examination was whenParticipant 7A was about 3 years and 4 months of age. Participant 7 hadno speech. Participant 7 was diagnosed with bilateral ankle clonus,bilateral Babinski and spastic dipligea. Participant 7 was in awheelchair. An MRI revealed brain damage consistent with cerebral palsy.

The second examination was when Participant 7 was 4½ years of age.Participant 7 remains in a wheelchair. Participant 7 was able to moveher legs but not sequentially while sitting in the wheelchair.Participant 7 has leg braces.

The third examination determined that Participant 7 is not healing wellbecause of the continued wearing of the leg braces.

The fourth examination was about three years after the thirdexamination. Participant 7 is about 8 years of age. One month prior tothe fourth examination, Participant 7 was prescribed 5 mg MPD/day. Atthe fourth examination, 5 mg MPD was administered. Participant 7, withassists, was able to get out of the wheelchair and had a somewhat moreappropriate posture. A regimen of 5 mg MPD in the morning and in theevening was prescribed.

The fifth examination was one month after the fourth examination. It wasreported by the mother and caretakers that Participant 7 was speakingmore than she had in the prior month. Participant 7 shows furtherimprovement in moving her legs in the wheelchair. The braces remain.

The sixth examination is one month after the fifth examination.Participant 7 is speaking more. The braces remain.

There is then a 2½ year hiatus during which there are no furtherexaminations or pharmaceutical administrations pursuant to the presentintervention. The examinations resumed after the 2½ year hiatus.

At the eleventh examination, the braces remain and appear to have beenin place essentially during the entire 2½ year hiatus. There were bracemarks on her legs as a result of the extended usage. The Participant 7legs became weaker. The Participant 7 sedentary life style in turncaused worsened or exacerbated pain in attempts to get out of thewheelchair and stand, and then walk with a walker.

In the course of subsequent visits (examinations 12^(th) and 13^(th)),in a period of about one month, Participant 7 was on a daily dosageregimen of 5 mg MPD, and then 5 mg Focalin®. Two weeks after theeleventh examination, it was agreed to remove the braces permanently.Two weeks thereafter, when Participant 7 had no longer been on MPD for24 hours, Participant 7A exhibited the ability to stand up from thewheelchair with greater ease, to more readily walk and turn with awalker. She was more able to lift her feet and was less prone totripping.

FIG. 10 shows the time spent (in seconds) unassisted in standing up fromthe wheelchair to a walker for Participant 7 during the 11^(th) (Apr.17, 2015), 12^(th) (May 1, 2015), and 13^(th) (May 22, 2015)examinations.

Referring specifically to FIGS. 10 and 11, Participant 7 was on aregimen of 5 mg/day Focalin® in a period from the May 1, 2015visit/examination to the May 22, 2015 visit/examination. FIGS. 10 and 11demonstrate the dramatic improvement with a Focalin® regimen over abouta three week period.

The Participant 7 Example demonstrates that a sustained regimen of MPDand particularly Focalin, with the removal of leg braces, effectedsignificant diminished impairment, particularly the ready ability tolift out of a wheelchair and use in a walker without tripping.

Participant 7 had accordingly improved from a level 5 GFMCS to a level 3GFMCS as shown in FIG. 2. This is a surprising and unexpected resultinasmuch as generally a child at GFMCS level 5 will not improve butremain at a GFMCS level 5.

Particularly suitable psychostimulants pursuant to the present inventioninclude the norephinephrine-dopamine reuptake inhibitors (NDRIs)including, by way of example, methylphenidate, modafinil, armodafiml anddextro-methylphenidate, as discussed in co-pending applicationPCT/US2012/038312, filed May 17, 2012, and U.S. Ser. No. 14/112,065,filed Oct. 16, 2013, incorporated herein by reference thereto. Extendedrelease, controlled release and immediate release forms methylphenidateare contemplated as useful psychostimulants. Immediate releasemethylphenidate is a preferred psychostimulant.

Preferred psychostimulants further include the lower alkyl phenidates,such as disclosed in Schweri et al., [³ H] Threo-(±)-MethylphenidateBinding to 3,4-Dihydroxyphenylethylamine Uptake Sites in CorpusStriatum: Correlation with the Stimulant Properties of Ritalinic AcidEsters, J. of Neurochemistry, vol. 45, no. 4, pp. 1062-70, (1985), andPortoghese et al, Relative Hydrolytic Rates of Certain Alkyl (b)dl-a-(2-Piperidl)-phenylacetrates, J. Pharmaceutical Science, vol. 50,no. 6, pp. 494-51, and U.S. Pat. No. 6,528,530, issued Mar. 4, 2003 toZeitlin, et al. Preferred psychostimulants also include the nonlinearlower alkyl phenidates, namely isopropyl, isobutyl, d-isoproyl,d-isobutyl, d-threo-isopropyl, d-threo, isopropyl, sec-butyl andt-butyl.

Alkyl phenidates, racemic mixtures and isolated individual isomers areknown in the art, as disclosed in U.S. Pat. No. 2,507,631, issued May16, 1950 to Hartmann et al, U.S. Pat. No. 2,157,880, issued Oct. 25,1960 to Rometsch, and U.S. Pat. No. 5,908,850 issued Jun. 1, 1999 toZeitlin et al; which references are incorporated herein in theirentireties by reference thereto. Alkyl phenidates are commerciallyavailable, including by way of example, dextro-threo-methylphenidate(Focalin®) and isopropylphenidate.

Without wishing to be bound by any theory or mechanism, it is believedthat the nonlinear lower alkyl phenidates provide hindrance tounwarranted esterfication which in turn causes adverse side effects,particularly adverse in children.

In the art related to the treatment of hyperactivity in children,particularly including ADD and ADHD, it is established practice toadminister methylphenidate. Psychosocial behavioral disorders such aslack of attentiveness and verbal regression are improved with theadministration of methylphenidate, as disclosed in U.S. Pat. No.6,121,261, issued Sep. 19, 2006 to Glatt et al; and Creager et al.,Journal of Speech and Hearing Research, 623-628 (1967). Methylphenidateis administered daily to children suffering psychobehavioral andneuropsychological disorders. The behavioral improvement is short lived,and lasts, at most, several hours after administration of themethylphenidate. Unless such daily dosages are maintained, the subjectreverts to his or her attention deficits and hyperactivity.

One further most preferred methylphenidate is an extended release powderin aqueous suspension as disclosed in US 2013/0004571A1, published Jan.3, 2013 to Metha et al., which is incorporated herein in its entirety byreference thereto. The aqueous suspension is particularly administrableto children with infantile cerebral palsy.

The foregoing Examples demonstrate that diseases or disorders,particularly including cerebral palsy and Rett syndrome having secondaryspeech and limits impairments are treated by the present invention.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inthe responsiveness of the subject being treated for any of theindications with the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compounds selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

What is claimed is:
 1. A pharmaceutical intervention for a gait or limbimpairment secondary to a non degenerative disease or disorder acquiredin utero, during birth or in infancy, in a subject in need of theintervention, wherein the limb or gait impairment is manifested later inthe life of the subject, said pharmaceutical intervention comprises: apsychostimulant having mood-elevating or anti-depressant activity;whereby the gait or limb impairment is diminished.
 2. The pharmaceuticalintervention of claim 1, wherein the psychostimulant comprises amethylphenidate.
 3. The pharmaceutical intervention of claim 2, whereinthe methylphenidate comprises dextro-threo-methylphenidate.
 4. Thepharmaceutical intervention of claim 2, wherein the methylphenidatecomprises an analog of methylphenidate.
 5. The pharmaceuticalintervention of claim 1, said psychostimulant comprises a non linearlower alkyl phenidate.
 6. The pharmaceutical intervention of claim 1,wherein said subject had a speech impairment comprising dysarthricspeech prior to the pharmaceutical intervention, and the dysarthricspeech impairment is diminished after the pharmaceutical intervention.7. The pharmaceutical intervention of claim 1, wherein the gaitimpairment comprises toe-to-heel gait.
 8. The pharmaceuticalintervention of claim 7, wherein the heel-to-toe gait is greater thantoe-to-heel gait after the pharmaceutical intervention.
 9. Thepharmaceutical intervention of claim 8, wherein the improved heel-to-toegait persists when the pharmaceutical intervention is no longerefficaciously present.
 10. The pharmaceutical intervention of claim 1,wherein the disease or disorder is genetically related.
 11. Apharmaceutical intervention for treating a gait impairment secondary tocerebral palsy or other disease or disorder, said impairment beingacquired in utero, at birth or in infancy but later manifested in asubject in need of such intervention, said pharmaceutical interventioncomprises: a psychostimulant having mood-elevating or anti-depressantproperties affecting neural pathway effecting gait; whereby the gaitimpairment is diminished.
 12. The pharmaceutical intervention of claim11, wherein the disease or disorder is genetically related.
 13. Thepharmaceutical intervention of claim 11, wherein the psychostimulantcomprises a methylphenidate.
 14. The pharmaceutical intervention ofclaim 13, wherein the methylphenidate comprisesdextro-threo-methylphenidate.
 15. The pharmaceutical intervention ofclaim 13, wherein the methylphenidate comprises an analog ofmethylphenidate.
 16. The pharmaceutical intervention of claim 11, saidpsychostimulant comprises a non linear lower alkyl phenidate.
 17. Thepharmaceutical intervention of claim 11, wherein the gait impairmentcomprises toe-to-heel gait.
 18. The pharmaceutical intervention of claim17, wherein the heel-to-toe gait is greater than toe-to-heel gait afterthe pharmaceutical intervention.
 19. The pharmaceutical intervention ofclaim 18, wherein the improved heel-to-toe gait persists when thepharmaceutical intervention is no longer efficaciously present.
 20. Amethod for treating a gait or limb impairment secondary to a nondegenerative disease or disorder acquired in utero, at birth or ininfancy but later manifested in a subject in need of such treatment,said method comprises (a) administering a therapeutically effective doseof a psychostimulant having mood-elevating or anti-depressant activityeffecting gait or limb neural pathways; whereby the gait or limbimpairment is diminished.
 21. The method of claim 20, wherein thedisease or disorder is binding protein limited.
 22. The method of claim20, wherein the psychostimulant comprises a methylphenidate.
 23. Themethod of claim 20, wherein the psychostimulant comprises amethylphenidate.
 24. The method of claim 20, wherein the methylphenidatecomprises dextro-threo-methylphenidate.
 26. A pharmaceuticalintervention for treating a toe drop impairment secondary to a diseaseor disorder in a subject in need of such treatment, said pharmaceuticalintervention comprises: a therapeutically effective dose of apsychostimulant, said psychostimulant having mood-elevating oranti-depressant activity; wherein the toe drop impairment is diminished.27. The pharmaceutical intervention of claim 25, wherein there isgreater heel-to-toe gait than toe-to-heel gait after the pharmaceuticalintervention.
 28. The pharmaceutical intervention of claim 25, whereinthe subject is a child.
 29. The pharmaceutical intervention of claim 25,wherein the subject has a speech impairment secondary to the disease ordisorder and the speech impairment is diminished with thepsychostimulant intervention.
 30. The pharmaceutical intervention ofclaim 25, wherein the diminishment of the impairment persist when thepsychostimulant is no longer efficaciously present.
 31. Thepharmaceutical intervention of claim 25, wherein the psychostimulantcomprises a methylphenidate.
 32. The pharmaceutical intervention ofclaim 31, wherein the methylphenidate comprises adextro-methylphenidate.
 33. The pharmaceutical intervention of claim 32,wherein the dextro-methylphenidate consists essentially ofdextro-threo-methylphenidate.
 34. The pharmaceutical intervention ofclaim 31, wherein the methylphenidate comprises a nonlinear lower alkylphenidate.
 35. The pharmaceutical intervention of claim 34, wherein thenonlinear lower alkyl phenidate comprises isopropylphenidate.
 36. Thepharmaceutical intervention of claim 25, wherein the impairment isgenetic cerebral palsy.
 37. A pharmaceutical intervention for treating aspasticity impairment secondary to cerebral palsy or othernon-degeneratiave disease or disorder acquired in utero, at birth or ininfancy, but later manifested in a subject in need of such intervention,said pharmaceutical intervention comprises: a psychostimulant havingmood-elevating or anti-depressant properties; whereby the spasticityimpairment is diminished.
 38. The pharmaceutical intervention of claim37, wherein the disease or disorder is genetically related.
 39. Thepharmaceutical intervention of claim 37, wherein the psychostimulantcomprises a methylphenidate.
 40. The pharmaceutical intervention ofclaim 37, wherein the spasticity impairment comprises spastic diplegia.41. The pharmaceutical intervention of claim 37, wherein thediminishment in the impairment persists when the psychostimulant is nolonger efficaciously present in the subject.
 42. A method for treating aspastic diplegia impairment resultant from an early in life acquirednon-degenerative disease or disorder in a subject in need of suchtreatment, said method comprises; (a) administering a therapeuticallyeffective dose of a psychostimulant having mood-elevating oranti-depressant activity; whereby the spastic diplegia impairment isdiminished.
 43. The method of claim 42, wherein the psychostimulantcomprises dextro-threo-methylphenidate.
 44. The method of claim 42,wherein the disease or disorder comprises cerebral palsy.
 45. The methodof claim 42, wherein the diminishment in the impairment persists whenthe psychostimulant is no longer efficaciously present in the subject.46. The method of claim 45, wherein the psychostimulant consistsessentially of dextro-threo-methylphenidate.
 47. The method of claim 42,wherein the psychostimulant comprises an NDRI.
 48. The method of claim42, wherein the psychostimulant comprises an analog of amethylphenidate.
 49. The method of claim 48, wherein the analog of amethylphenidate comprises a nonlinear lower alkyl methylphenidate. 50.The method of claim 49, wherein the nonlinear lower alkylmethylphenidate comprises isopropylphenidate.
 51. The method of claim42, wherein the subject has a dysarthric speech impairment secondary tothe disease or disorder, and wherein the method effects a diminishmentin the dysarthric speech impairment.
 52. The method of claim 42, whereinthe spastic diplegia is acquired in utero, during childbirth or ininfancy and manifested later in the life of the subject.
 53. The methodof claim 42, wherein the subject has a dysarthric speech impairmentsecondary to the disease or disorder, wherein the method effects adiminishment in the dysarthric speech impairment, and wherein thespastic diplegia is acquired in utero, during childbirth or in infancyand manifested later in the life of the subject.
 54. The method of claim53, wherein at least one of the impairments is manifested when thesubject is a child.
 55. The method of claim 53, wherein thepsychostimulant comprises dextro-threo-methylphenidate.